Difluoromethylated Difunctionalization of Alkenes under Visible Light.

Difluoromethylated compounds usually act as bioisosteres for alcohol functional groups and show unique physicochemical and biological properties. The cyano-difluoromethylation of alkenes using 5-((difluoromethyl)sulfonyl)-1-phenyl-1H-tetrazole as a CF2H radical difluoromethyl precursor was developed to afford nitriles including a CF2H group. A low-cost, stable, easily handled 5-((difluoromethyl)sulfonyl)-1-methyl-1H-tetrazole (DFSMT) was synthesized and applied as the radical CF2H reagent. Using DFSMT as the radical CF2H precursor, the oxyl-difluoromethylation of alkenes was developed to obtain difluoromethylated ether products. All of the reactions showed good functional group tolerability. Initial mechanistic experiments indicated that the CF2H radical was involved as the key active intermediate.

Application of the Interagency and Modeling Analysis Group Model Verification Approach for Scientific Reproducibility in a Study of Biomineralization.

Model verification is a critical aspect of scientific accountability, transparency, and learning. Here, we demonstrate an application of a model verification approach for a molecular dynamics (MD) simulation, where the interactions between silica and silk protein were studied experimentally toward understanding biomineralization. Following the ten rules for credible modeling and simulation of biosciences as developed in Erdemir et al., the authors of the original paper collaborated with an external modeling group to verify the key findings of their original simulation model and to document this verification approach. The process resulted in successful replication of the key findings of the original model. Beyond verification, study of the model from a new perspective generated new insight into the basic assumptions. We discuss key learnings for how model validation processes can be improved more generally, specifically through improved documentation methods. We anticipate that this application of our protocol for model verification can be further replicated and improved to verify and validate other simulations.

A Comprehensive Review of Natural Flavonoids with Anti-SARS-CoV-2 Activity.

The COVID-19 pandemic caused by SARS-CoV-2 has majorly impacted public health and economies worldwide. Although several effective vaccines and drugs are now used to prevent and treat COVID-19, natural products, especially flavonoids, showed great therapeutic potential early in the pandemic and thus attracted particular attention. Quercetin, baicalein, baicalin, EGCG (epigallocatechin gallate), and luteolin are among the most studied flavonoids in this field. Flavonoids can directly or indirectly exert antiviral activities, such as the inhibition of virus invasion and the replication and inhibition of viral proteases. In addition, flavonoids can modulate the levels of interferon and proinflammatory factors. We have reviewed the previously reported relevant literature researching the pharmacological anti-SARS-CoV-2 activity of flavonoids where structures, classifications, synthetic pathways, and pharmacological effects are summarized. There is no doubt that flavonoids have great potential in the treatment of COVID-19. However, most of the current research is still in the theoretical stage. More studies are recommended to evaluate the efficacy and safety of flavonoids against SARS-CoV-2.

A D-cysteine desulfhydrase, SlDCD2, participates in tomato fruit ripening by modulating ROS homoeostasis and ethylene biosynthesis.

Hydrogen sulfide (H2S) is involved in multiple processes during plant growth and development. D-cysteine desulfhydrase (DCD) can produce H2S with D-cysteine as the substrate; however, the potential developmental roles of DCD have not been explored during the tomato lifecycle. In the present study, SlDCD2 showed increasing expression during fruit ripening. Compared with the control fruits, the silencing of SlDCD2 by pTRV2-SlDCD2 accelerated fruit ripening. A SlDCD2 gene-edited mutant was constructed by CRISPR/Cas9 transformation, and the mutant exhibited accelerated fruit ripening, decreased H2S release, higher total cysteine and ethylene contents, enhanced chlorophyll degradation and increased carotenoid accumulation. Additionally, the expression of multiple ripening-related genes, including NYC1, PAO, SGR1, PDS, PSY1, ACO1, ACS2, E4, CEL2, and EXP was enhanced during the dcd2 mutant tomato fruit ripening. Compared with the wild-type fruits, SlDCD2 mutation induced H2O2 and malondialdehyde (MDA) accumulation in fruits, which led to an imbalance in reactive oxygen species (ROS) metabolism. A correlation analysis indicated that H2O2 content was strongly positively correlated with carotenoids content, ethylene content and ripening-related gene expression and negatively correlated with the chlorophyll content. Additionally, the dcd2 mutant showed earlier leaf senescence, which may be due to disturbed ROS homeostasis. In short, our findings show that SlDCD2 is involved in H2S generation and that the reduction in endogenous H2S production in the dcd2 mutant causes accelerated fruit ripening and premature leaf senescence. Additionally, decreased H2S in the dcd2 mutant causes excessive H2O2 accumulation and increased ethylene release, suggesting a role of H2S and SlDCD2 in modulating ROS homeostasis and ethylene biosynthesis.

The fibrous character of pericellular matrix mediates cell mechanotransduction.

Cells in solid tissues sense and respond to mechanical signals that are transmitted through extracellular matrix (ECM) over distances that are many times their size. This long-range force transmission is known to arise from strain-stiffening and buckling in the collagen fiber ECM network, but must also pass through the denser pericellular matrix (PCM) that cells form by secreting and compacting nearby collagen. However, the role of the PCM in the transmission of mechanical signals is still unclear. We therefore studied an idealized computational model of cells embedded within fibrous collagen ECM and PCM. Our results suggest that the smaller network pore sizes associated with PCM attenuates tension-driven collagen-fiber alignment, undermining long-range force transmission and shielding cells from mechanical stress. However, elongation of the cell body or anisotropic cell contraction can compensate for these effects to enable long distance force transmission. Results are consistent with recent experiments that highlight an effect of PCM on shielding cells from high stresses. Results have implications for the transmission of mechanical signaling in development, wound healing, and fibrosis.

Asymmetric Construction of an Aryl-Alkene Axis by Palladium-Catalyzed Suzuki-Miyaura Coupling Reaction.

The application of Suzuki-Miyaura coupling reaction to forge the atropisomeric biaryls has seen remarkable progress but exploration of this chemistry to directly forge chiral C(aryl)-C(alkene) axis is underdeveloped. The replacement of arene substrates by alkenes intensifies the challenges in terms of reactivity, configurational atropostability of product and selectivity control. By meticulous ligand design and fine-tuning of reaction parameters, we identified a highly active 3,3'-triphenylsilyl-substituted phosphite ligand to realize arene-alkene Suzuki-Miyaura coupling of hindered aryl halides and vinyl boronates under very mild conditions. The axially chiral acyclic aryl-alkenes were generated in commendable efficiency, enantioselectivity and E/Z selectivity.

Acoustic radiation force on a long cylinder, and potential sound transduction by tomato trichomes.

Acoustic transduction by plants has been proposed as a mechanism to enable just-in-time up-regulation of metabolically expensive defensive compounds. Although the mechanisms by which this "hearing" occurs are unknown, mechanosensation by elongated plant hair cells known as trichomes is suspected. To evaluate this possibility, we developed a theoretical model to evaluate the acoustic radiation force that an elongated cylinder can receive in response to sounds emitted by animals, including insect herbivores, and applied it to the long, cylindrical stem trichomes of the tomato plant Solanum lycopersicum. Based on perturbation theory and validated by finite element simulations, the model quantifies the effects of viscosity and frequency on this acoustic radiation force. Results suggest that acoustic emissions from certain animals, including insect herbivores, may produce acoustic radiation force sufficient to trigger stretch-activated ion channels.

An ex vivo culture model of kidney podocyte injury reveals mechanosensitive, synaptopodin-templating, sarcomere-like structures.

Chronic kidney diseases are widespread and incurable. The biophysical mechanisms underlying them are unclear, in part because material systems for reconstituting the microenvironment of relevant kidney cells are limited. A critical question is how kidney podocytes (glomerular epithelial cells) regenerate foot processes of the filtration apparatus following injury. Recently identified sarcomere-like structures (SLSs) with periodically spaced myosin IIA and synaptopodin appear in injured podocytes in vivo. We hypothesized that SLSs template synaptopodin in the initial stages of recovery in response to microenvironmental stimuli and tested this hypothesis by developing an ex vivo culture system that allows control of the podocyte microenvironment. Results supported our hypothesis. SLSs in podocytes that migrated from isolated kidney glomeruli presented periodic synaptopodin-positive clusters that nucleated peripheral, foot process-like extensions. SLSs were mechanoresponsive to actomyosin inhibitors and substrate stiffness. Results suggest SLSs as mechanobiological mediators of podocyte recovery and as potential targets for therapeutic intervention.

Visible-Light-Induced, Graphene Oxide-Promoted C3-Chalcogenylation of Indoles Strategy under Transition-Metal-Free Conditions.

An efficient and general method for the synthesis of 3-sulfenylindoles and 3-selenylindoles employing visible-light irradiation with graphene oxide as a promoter at room temperature has been achieved. The reaction features are high yields, simple operation, metal-free and iodine-free conditions, an easy-to-handle oxidant, and gram-scalable synthesis. This simple protocol allows one to access a wide range of 3-arylthioindoles, 3-arylselenylindoles, and even 3-thiocyanatoindoles with good to excellent yields.

Photoinitiated Multicomponent Anti-Markovnikov Alkoxylation over Graphene Oxide.

The development of graphene oxide-based heterogeneous materials with an economical and environmentally-friendly manner has the potential to facilitate many important organic transformations but proves to have few relevant reported reactions. Herein, we explore the synergistic role of catalytic systems driven by graphene oxide and visible light that form nucleophilic alkoxyl radical intermediates, which enable an anti-Markovnikov addition exclusively to the terminal alkenes, and then the produced benzyl radicals are subsequently added with N-methylquinoxalones. This photoinduced cascade radical difunctionalization of olefins offers a concise and applicable protocol for constructing alkoxyl-substituted N-methylquinoxalones.

Roles of a Cysteine Desulfhydrase LCD1 in Regulating Leaf Senescence in Tomato.

Hydrogen sulfide (H2S), a novel gasotransmitter in both mammals and plants, plays important roles in plant development and stress responses. Leaf senescence represents the final stage of leaf development. The role of H2S-producing enzyme L-cysteine desulfhydrase in regulating tomato leaf senescence is still unknown. In the present study, the effect of an L-cysteine desulfhydrase LCD1 on leaf senescence in tomato was explored by physiological analysis. LCD1 mutation caused earlier leaf senescence, whereas LCD1 overexpression significantly delayed leaf senescence compared with the wild type in 10-week tomato seedlings. Moreover, LCD1 overexpression was found to delay dark-induced senescence in detached tomato leaves, and the lcd1 mutant showed accelerated senescence. An increasing trend of H2S production was observed in leaves during storage in darkness, while LCD1 deletion reduced H2S production and LCD1 overexpression produced more H2S compared with the wild-type control. Further investigations showed that LCD1 overexpression delayed dark-triggered chlorophyll degradation and reactive oxygen species (ROS) accumulation in detached tomato leaves, and the increase in the expression of chlorophyll degradation genes NYC1, PAO, PPH, SGR1, and senescence-associated genes (SAGs) during senescence was attenuated by LCD1 overexpression, whereas lcd1 mutants showed enhanced senescence-related parameters. Moreover, a correlation analysis indicated that chlorophyll content was negatively correlated with H2O2 and malondialdehyde (MDA) content, and also negatively correlated with the expression of chlorophyll degradation-related genes and SAGs. Therefore, these findings increase our understanding of the physiological functions of the H2S-generating enzyme LCD1 in regulating leaf senescence in tomato.

Light-driven selective aerobic oxidation of (iso)quinoliniums and related heterocycles.

Selective C1-H/C4-H carbonylation of N-methylene iminium salts, catalyzed by visible-light photoredox and oxygen in the air, has been reported. A ruthenium complex acts as a chemical switch to conduct two different reaction pathways and to afford two different kinds of products. In the absence of the ruthenium complex, the Csp2-H bonds adjacent to the nitrogen atoms are oxidized to α-lactams by the N-methyleneiminium substrates themselves as photosensitizers. In the presence of the ruthenium complex, the oxidation reaction site of quinoliniums is switched to the C4 region, resulting in the formation of 4-quinolones. The use of two transformations directly introduces oxygen into the nitrogen heterocyclic skeletons under an air atmosphere.

Graphene oxide-catalyzed trifluoromethylation of alkynes with quinoxalinones and Langlois' reagent.

The direct C-H trifluoromethylation of alkynes and quinoxalinones has been achieved using a graphene oxide/Langlois' reagent system. This multi-component tandem reaction using graphene oxide as the catalyst and Langlois' reagent as the robust CF3 radical source results in the formation of olefinic C-CF3 to access a series of 3-trifluoroalkylated quinoxalin-2(1H)-ones.

Sound absorption theory for micro-perforated panel with petal-shaped perforations.

Micro-perforated panel (MPP) absorbers with circular perforations are used in many noise control applications due to their attractive wide-brand sound absorption performance. Different from a common MPP with circular perforations, a unique type of MPP absorber with petal-shaped perforations is proposed. The sound absorption theory for the MPP with petal-shaped perforations is developed by accurately considering the fluid velocity in the petal-shaped perforation hole. This theory can account for the effect of altered perforation morphology (from circular to petal) on sound absorption. Finite element simulations are performed to validate the proposed theory, with good agreement achieved. The sound absorption of MPP with petal-shaped perforations is compared with that of the traditional MPP with the same porosity. It is demonstrated that the change in hole shape significantly modifies the fluid velocity field and the flow resistivity in/of the hole, and hence the sound absorption of the proposed MPP with petal-shaped perforations can outperform that of the traditional MPP in the considered case. This work proposes a general MPP theory that not only contains the classical Maa's theory for circular MPP, but also accounts for the MPP with petal-shaped perforations.

The acoustic radiation force of a focused ultrasound beam on a suspended eukaryotic cell.

Although ultrasound tools for manipulating and permeabilizing suspended cells have been available for nearly a century, accurate prediction of the distribution of acoustic radiation force (ARF) continues to be a challenge. We therefore developed an analytical model of the acoustic radiation force (ARF) generated by a focused Gaussian ultrasound beam incident on a eukaryotic cell immersed in an ideal fluid. The model had three layers corresponding to the nucleus, cytoplasm, and membrane, of a eukaryotic cell. We derived an exact expression for the ARF in relation to the geometrical and acoustic parameters of the model cell components. The mechanics of the cell membrane and nucleus, the relative width of the Gaussian beam, the size, position and aspect ratio of the cell had significant influence on the ARF. The model provides a theoretical basis for improved acoustic control of cell trapping, cell sorting, cell assembly, and drug delivery.

Correction of bias in the estimation of cell volume fraction from histology sections.

Accurate determination of the fraction of a tissue's volume occupied by cells is critical for studying tissue development, pathology, and biomechanics. For example, homogenization methods that predict the function and responses of tissues based upon the properties of the tissue's constituents require estimates of cell volume fractions. A common way to estimate cellular volume fraction is to image cells in thin, planar histologic sections, and then invoke either the Delesse or the Glagolev principle to estimate the volume fraction from the measured area fraction. The Delesse principle relies upon the observation that for randomly aligned, identical features, the expected value of the observed area fraction of a phase equals the volume fraction of that phase, and the Glagolev principle relies on a similar observation for random rather than planar sampling. These methods are rigorous for analysis of a polished, opaque rock sections and for histologic sections that are thin compared to the characteristic length scale of the cells. However, when histologic slices cannot be cut sufficiently thin, a bias will be introduced. Although this bias - known as the Holmes effect in petrography - has been resolved for opaque spheres in a transparent matrix, it has not been addressed for histologic sections presenting the opposite problem, namely transparent cells in an opaque matrix. In this note, we present a scheme for correcting the bias in volume fraction estimates for transparent components in a relatively opaque matrix.

Synthesis of imidazo[1,2-c]thiazoles through Pd-catalyzed bicyclization of tert-butyl isonitrile with thioamides.

Building new biological molecules is challenging. Herein, imidazo[1,2-c]thiazoles were synthesized as a new class of heterobicyclic analogs through Pd-catalyzed cascade bicyclization from isonitriles with thioamides. The bicyclic scaffolds were constructed by inserting three molecules of isonitrile into two molecules of thioamide and then cyclizing them in a one-pot procedure. In vitro antitumor studies of these new compounds were conducted by using the MTT assay, and compound 3c showed excellent inhibitory effects against HepG2 at 7.06 ± 0.68 µM.

CoCl2-promoted TEMPO oxidative homocoupling of indoles: access to tryptanthrin derivatives.

A novel TEMPO/CoCl2-promoted aerobic oxidation of indoles was developed. The reaction provided one-step access to tryptanthrin derivatives in moderate to good yields and excellent regioselectivity via a cascade process. The reactions could be carried out under mild reaction conditions with varying functional group tolerance, especially halogen functional groups. Mechanistic studies disclosed that the oxygen atom in the desired product originated from molecular dioxygen.

Regioselective synthesis of 2,3'-biindoles mediated by an NBS-induced homo-coupling of indoles.

Mild conditions have been developed to achieve NBS-induced homodimerization of indole derivatives with excellent regioselectivity at 15 °C in high efficiency. This method provides a simple route to a 2,3'-linked biindolyl scaffold from the electron-rich to moderately electron-poor indoles. In addition, [3,2-a]carbazole derivatives can also be prepared through this method.